Methamphetamine (MA) use can alter judgment, increase unsafe behaviors and violence, and cause mood disturbances. Chronic use is associated with paranoia, as well as visual and auditory hallucinations. A number of indicators point to increasing availability and abuse of MA in the United States, especially in the southern and western regions, among both young and older adults. MA is often taken in repeated binge- level doses, and individuals who become addicted to MA suffer high rates of relapse, even after prolonged periods of abstinence. MA is a neurotoxin when higher amounts are taken. Risk as a population measure can be assessed in animal models in the absence of drug exposure through a number of strategies, including the use of selectively bred animal lines. The Richards laboratory has developed an animal model of binge-like MA intake to study genetic risk, neurotoxicity, and changes in behavioral effects of MA associated with this high level of intake. That model, in concert with a genetic model of resistance to MA intake that was also developed in the Richards lab, was used to identify trace amine-associated receptor 1 (Taar1) as a gene that accounts for >50% of the genetic variance in MA intake. The high risk allele codes for a non-functional version of the receptor. However, whereas on an isogenic background, Taar1 allele type accounts for 92% of the phenotypic variance, it accounts for only 68% of the phenotypic variance on a mixed genetic background. Furthermore, some individuals that are homozygous for the high risk Taar1 allele retain a low MA intake profile. In addition to examining neurotoxicity associated with binge-level MA exposure and with differential Taar1 genotype, a focus of this research program will be on the identification of mechanisms, through transcriptome analyses, that protect against binge-level MA intake in individuals known to possess a high-risk Taar1 genotype; in other words to identify genetic modifiers. In Aim 1, controlled binge-level MA dosing and voluntary binge-level MA intake will be compared for their neurotoxic effects in a high MA intake selected mouse line and in mice of the high MA intake line in which the Taar1 allele that promotes high MA intake has been replaced with the protective allele, a genetic knock-in approach. In Aim 2, the impact of voluntary binge-level MA intake on conditioned-reward and a reliable physiological response to MA ? body temperature change ? will be examined. In Aim 3, a new genetic model will be developed comprised of bidirectionally selected lines derived from individuals that are all homozygous for the Taar1 MA risk allele, but are bred for high vs. low MA intake. Although listed as Aim 3, the production of these lines will begin early in the research program so that they are available for use by year 3. These lines will also be characterized for MA reward, temperature change, tastant preference and MA clearance rate. Finally, in Aim 4, analyses will be conducted using tissues from the selected lines to identify differences in the transcriptome that predict an attenuation of the Taar1 allele effect on MA intake. Tissues from saline- and MA-treated animals will be used. Because there is evidence for human TAAR1 allelic differences that impact receptor function, this is an exciting research direction that could lead to the identification of protective factors that alleviate genetic risk for binge-level MA intake and ultimately to new and more effective treatments.